ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12618000877280

Ethics application status

Approved

Date submitted

24/04/2018

Date registered

23/05/2018

Date last updated

12/07/2022

Date data sharing statement initially provided

23/04/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

Phase 1b clinical trial testing whether cimetidine prevents hearing loss from cisplatin chemotherapy in head and neck cancer patients

Scientific title

Phase Ib randomised, placebo-controlled, double-blinded trial using Cimetidine to prevent the Oto-, Nephro- and neuro-toxicity of Cisplatin by OCT2 inhibition in patients undergoing chemoradiation for head and neck cancer

Secondary ID [1]

None

Universal Trial Number (UTN)

U1111-1212-8274

Trial acronym

CONCOCT

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Chemotherapy toxicity

Condition category

Condition code

Cancer

Head and neck

Ear

Deafness

Neurological

Other neurological disorders

Renal and Urogenital

Kidney disease

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Patients will take cimetidine 800mg (2 x 400mg capsules) orally 30 minutes before, and again 90 minutes after, the start of each cisplatin infusion. This will be repeated every 3 weeks for 3 cycles of chemotherapy. The study medication will be administered under nursing supervision.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Patients will take 2 x placebo capsules (containing microcellulose) orally 30 minutes before, and again 90 minutes after, the start of each cisplatin infusion. This will be repeated every 3 weeks for 3 cycles of chemotherapy. The study medication will be administered under nursing supervision.

Control group

Placebo

Outcomes

Primary outcome [1]

Mean change in hearing thresholds (averaged across 4000 Hz and 8000 Hz in both ears) between pretreatment baseline audiogram and an audiogram performed 3 months after completion of chemoradiation

Timepoint [1]

3 months after completion of chemoradiation

Secondary outcome [1]

Mean change in hearing thresholds (averaged for both ears) at each measured frequency between pretreatment baseline audiogram and an audiogram performed after each cycle of cisplatin

Timepoint [1]

At 3 and 6 weeks after starting study treatment, and again 3 months after completing chemoradiation

Secondary outcome [2]

Mean change in hearing thresholds (averaged across 4000 Hz and 8000 Hz in both ears) between pretreatment baseline audiogram and an audiogram performed 3 months after completion of chemoradiation, expressed as decibels lost per 100 mg/m2 of cisplatin

Timepoint [2]

3 months post-chemoradiation

Secondary outcome [3]

Proportion of patients with change in hearing loss categorised by Chang’s criteria and distortion-product otoacoustic emissions

Timepoint [3]

3 months post-chemoradiation

Secondary outcome [4]

Patient-reported outcomes for hearing, tinnitus and peripheral neuropathy, assessed as the proportion of patients who report the presence of, or treatment-emergent changes in, symptoms in these questionnaires: 1) the Tinnitus subscale for chemotherapy-induced neurotoxicity, 2) FACT/GOG neurotoxicity sensory subscale and 3) the Hearing Handicap Inventory for the Elderly

Timepoint [4]

3 and 6 weeks from starting study treatment and 3 months post-chemoradiation

Secondary outcome [5]

Renal injury from cisplatin as assessed by serial measurements of serum creatinine, magnesium and cystatin c, compared to baseline

Timepoint [5]

3 and 6 weeks from starting study treatment and 3 months post-chemoradiation

Secondary outcome [6]

Treatment-emergent adverse events (e.g. nausea, mucositis) graded according to the National Cancer Institute's Common Toxicity Criteria for Adverse Events version 4.

Timepoint [6]

3 and 6 weeks from starting study treatment and 3 months post-chemoradiation

Secondary outcome [7]

Cumulative cisplatin dose administered over the duration of chemoradiation (expressed in mg/m2) assessed from medical records

Timepoint [7]

End of study treatment (7 weeks after starting)

Secondary outcome [8]

Radiation dose delivered (measured in Grays) as a proportion of that intended in the treatment plan for each patient, assessed from medical records

Timepoint [8]

End of study treatment (7 weeks after starting)

Secondary outcome [9]

Cumulative number of days on which radiation treatment was delayed, assessed from medical records

Timepoint [9]

End of study treatment (7 weeks after starting)

Secondary outcome [10]

Total radiation dose administered to the inner ear on each side calculated from the radiation treatment plan and final radiation doses administered, assessed from medical records

Timepoint [10]

End of study treatment (7 weeks after starting)

Secondary outcome [11]

Ratio of plasma unbound cisplatin and cimetidine concentrations at the end of the cisplatin infusion

Timepoint [11]

At the end of the cisplatin infusion in Week 1

Secondary outcome [12]

Mean change in hearing thresholds (as per the primary outcome) in cimetidine and control groups according to patient SLC22A2 genotype (of 11 single nucleotide polymorphisms tested)

Timepoint [12]

After assessment of the primary outcome (i.e. at least 3 months after completion of treatment in all patients)

Eligibility

Key inclusion criteria

• pathologically-confirmed locally-advanced HNSCC for which concurrent chemoradiation using cisplatin 100mg/m2 every 3 weeks for 3 cycles is planned
• adequate baseline renal function (estimated glomerular filtration rate >60 ml/min)
• adequate baseline hepatic and bone marrow function;
• have signed written, informed consent

Minimum age

15 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

• planned to receive platinum-based chemotherapy before or after radiation
• prior chemotherapy with cisplatin or platinum analogues
• existing hearing loss > 50 dB between 2000 and 8000 Hz, or hearing aids needed
• radiation treatment plan would result in a cochlear dose > 45 Gy in either ear
• allergic to cimetidine
• taking drugs that are substrates of OCT2 (organic cation transporter type 2) unless the medication can safely be omitted on each day of cisplatin and cimetidine administration
• taking medications with which cimetidine is known to have clinically-significant drug-drug interactions
• congenital or acquired long QT syndrome
• co-morbidities that would preclude cisplatin use, such as cardiac failure
• pregnant or breastfeeding.

Study design

Purpose of the study

Prevention

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Treatment allocation will be by sealed envelopes held by a central pharmacy (off-site)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Permuted block randomisation

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Parallel

Other design features

Phase

Phase 1

Type of endpoint/s

Efficacy

Statistical methods / analysis

The expected acquired mean hearing loss at 4000 Hz and 8000 Hz (primary endpoint) in the placebo group is 20 dB. Using a two-sample comparison of means, a sample size of 30 randomised patients (15 in each arm) recruited over 2 years, with one dropout in each arm, gives the trial 90% power to detect a 5 dB difference in the mean hearing loss at these frequencies in the cimetidine group compared to the placebo group, with two-sided a=0.05. If up to 4 patients drop out of each arm the trial has 80% power to detect the specified difference in mean hearing loss.

The primary analysis will be based on an Intention-to-treat analysis. A per-protocol sensitivity analysis will also be conducted, excluding those patients not taking any cimetidine/placebo and evaluating mean change in hearing thresholds per 100 mg/m2 cisplatin administered.

The primary outcome is hearing loss at 4000 Hz and 8000 Hz averaged across both ears at 3 months post-CRT compared to baseline, and analysis will be by paired t test. A two-tailed p < 0.05 will indicate statistical significance.

All secondary analyses are hypothesis-generating, and no adjustments will be made for multiple comparisons. The secondary endpoints expressed as proportions will be reported as means, along with the mean differences, corresponding 95% confidence intervals and p-values, based on exact binomial distributions. Analyses will use t-tests to compare groups. For categorical outcomes chi-square tests will be used to compare groups. Adverse events in each arm will be tabulated and graded according to the NCI CTCAE version 4.03.

The mean ratio of unbound plasma cimetidine to cisplatin will be calculated and reported along with 95% confidence intervals. Repeated measures ANOVA will be used to analyse changes in renal function, hearing at individual frequencies and patient-reported outcomes over time.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

1/11/2018

Actual

15/08/2019

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

Accrual to date

Final

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Auckland and Waikato

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Cancer Research Trust New Zealand

Address [1]

56 Whitehaven Road
Glendowie
Auckland 1071

Country [1]

New Zealand

Primary sponsor type

Individual

Name

Associate Professor Michael Jameson

Address

University of Auckland Waikato Clinical Campus
Private Bag 3200
Hamilton 3240

Country

New Zealand

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Northern A Health and Disability Ethics Committee

Ethics committee address [1]

Ministry of Health
 Health and Disability Ethics Committees
 PO Box 5013
 Wellington 6140

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

05/09/2018

Approval date [1]

06/11/2018

Ethics approval number [1]

Summary

Brief summary

Patients with cancers of the head and neck are often cured with cisplatin chemotherapy and radiotherapy but this can lead to permanent reduction in hearing and kidney function. This trial will study if the drug cimetidine can protect kidneys and hearing from damage due to cisplatin chemotherapy in patients having this treatment for head and neck cancer. If cimetidine is found to be protect against these side effects in this group of patients, further trials will be undertaken to see if it may also be helpful to the many adults and children receiving cisplatin chemotherapy for other types of cancer.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

A/Prof Michael Jameson

Address

University of Auckland Waikato Clinical Campus
Private Bag 3200
Hamilton 3240

Country

New Zealand

Phone

+64 7 839 8976

Fax

+64 7 858 0940

michael.jameson@waikatodhb.health.nz

Contact person for public queries

Name

Navin Wewala

Address

Palmerston North Hospital
50 Ruahine Street
Private Bag 11036
Palmerston North 4442

Country

New Zealand

Phone

+64 6 350 9159

Fax

+64 6 350 8131

Navin.Wewala@midcentraldhb.govt.nz

Contact person for scientific queries

Name

Michael Jameson

Address

University of Auckland Waikato Clinical Campus
Private Bag 3200
Hamilton 3240

Country

New Zealand

Phone

+64 7 839 8976

Fax

+64 7 858 0940

michael.jameson@waikatodhb.health.nz

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

Individual participant data underlying published results only

When will data be available (start and end dates)?

Immediately following publication, no end date

Available to whom?

Case-by-case basis at the discretion of Primary Investigator

Available for what types of analyses?

Only to achieve the aims in the approved proposal

How or where can data be obtained?

Access subject to approvals by Principal Investigator (michael.jameson@waikatodhb.health.nz)

What supporting documents are/will be available?

Doc. No.	Type	Email
11458	Study protocol	michael.jameson@waikatodhb.health.nz
11459	Statistical analysis plan	michael.jameson@waikatodhb.health.nz
11460	Informed consent form	michael.jameson@waikatodhb.health.nz
11461	Clinical study report	michael.jameson@waikatodhb.health.nz
11462	Ethical approval	michael.jameson@waikatodhb.health.nz

Results publications and other study-related documents

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